Androgens demonstrate the various functions in the promotion of sexual differentiation and the induction of male phenotype. In males, the high active endogenous androgens in mediating these functions are testosterone (T) and 5α-dihydrotestosterone (DHT).
Plasma T levels decline linearly and progressively in men with aging at the rate of about 1% per year starting from their early twenties (Metabolism, 46, 410-413; J. Clin. Endocrinol. Metab., 86, 724-731; J. Clin. Endocrinol. Metab., 87, 589-598). This decline in the bioavailable T is thought to be associated with changes in a body fat distribution, diminished energy expenditure, diminished muscle strength and bone density, diminished physical function, reduced sexual function and depressed mood (J. Gerontol., 57A, M76-M99; Endocrine Rev., 26, 833-876; Med. Hypoth., 60, 448-452; J. Alzheimer's Dis., 5, 267-269; Cell. Mol. Life Sci., 62, 281-292). This androgen-deficient state in the aging males is often called andropause or late-onset hypogonadism (LOH). Androgen therapy, using an injectable, oral, and more recently, transdermal preparation, has been used for many years for the various male disorders. Several clinical studies have shown that the supplementation of T at physiologic doses in the elderly men results in a significant increase in a lean body mass, a decrease in adipose tissue, and an increase in muscle strength and bone density (J. Clin. Endocrinol. Metab., 84, 2647-2653; Am. J. Physiol. Endocrinol. Metab., 282, E601-E607; J. Am. Med. Assoc., 288, 2282-2292; Am. J. Physiol. Endocrinol. Metab., 284, E120-E128; J. Clin. Endocrinol. Metab., 90, 678-688; J. Clin. Endocrinol. Metab., 90, 1502-1510).
However, testosterone (T) replacement therapy in the elderly males is often limited due to concerns over potential side effects including a hyperstimulation of the prostate, increased hematocrit, liver dysfunction and sleep apnea syndrome (Am. J. Med., 110, 563-572; J. Am. Geriat. Soc., 51, 101-115; N. Engl. J. Med., 350, 482-492; J. Clin. Endocrinol. Metab., 89, 4789-4796; Ann. Rev. Med., 56, 117-137). In particular, there is concern over hyperstimulation of the prostate leading to occult, subclinical benign prostate hypertrophy (BPH) or prostate cancer. Consequently, it is extremely important to develop compounds having a distinct tissue specificity corresponding to a particular disease. Such a compound is referred to as a selective androgen receptor modulator (SARM) (J. Clin. Endocrinol. Metab., 84, 3459-3462), and this compound has the potential to maintain or improve the muscle strength and muscle function, prevent the osteoporosis and/or fractures by increasing the bone density, demonstrate the anti-obesity activity, demonstrate the anti-diabetic activity and/or anti-hyperlipemic activity by improving the insulin sensitivity, demonstrate the anti-dementia activity and improve the libido and sexual function in the elderly men in particular without the concomitant deleterious effects on the prostate, liver or erythrocytes that are commonly associated with the steroid treatment regimens.
Androgen receptors (AR) are the transcription factors that are also the members of the family of nuclear receptors. AR are widely distributed in the reproductive and non-reproductive tissues, including the prostate gland and seminal vesicles, male and female external genitalia, testes, ovaries, skin, cardiac muscle, skeletal muscle, liver, and brain cortical or subcortical regions. Despite this wide-ranging distribution of AR, natural ligands in the form of dihydrotestosterone and synthetic AR ligands demonstrate the different activities. This is because the types and concentrations of cofactors (co-activators or co-repressors) present within the cell nuclei differ depending to the type of each tissue or cell, and as a result of the differences in the complex formation occurring due to the co-activator or co-repressor binding, AR are able to selectively control the individual genes in the specific tissues. Recently, the details of a transcription control mechanism of a complex consisting of a ligand-nuclear receptor formed by binding with a ligand, and a co-activator or co-repressor have been elucidated. If the structure of the ligand differs, then the three-dimensional structure of the ligand-nuclear receptor complex also differs, which in turn also results in the differences in binding to a co-activator or co-repressor. Thus, since SARMs have the specific, partial agonistic activity that induces the various forms of transcription control in the different tissues and cells, they are expected to lead to the development of novel therapeutic drugs having the unique activity profiles.
Compounds that do not act on the prostate but exhibit the activities on the muscle or bone have previously been reported that were developed starting from the known AR antagonists bicalutamide and flutamide (J. Med. Chem., 49, 7596-7599). Various other compounds are also known to be SARMs (for example, Japanese Unexamined Patent Publication No. 2007-211024, Japanese Translation of PCT International Application Publication No. 2007-526336, Japanese Translation of PCT International Application Publication No. 2008-501800). Although the activities of SARMs are used for the various purposes, for example, in the case of the elderly men suffering from osteopenia or osteoporosis, if the target site is the bone of those men, a more anabolic SARM with a clear activity on the bone and muscle, but a lesser activity on the prostate and other sex accessory organs is desired.